炎症是针对内源性和外源性病原体的保护机制。它是许多慢性疾病及其并发症的典型特征。Keap1是氧化应激和炎性疾病的重要靶点。其中,Keap1-Nrf2-ARE途径(包括Keap1-Nrf2-HO-1)是Keap1靶标的最重要途径,参与控制多个器官的炎症(包括肾脏炎症,肺部炎症,肝脏炎症,神经炎症,等。).确定新的Keap1抑制剂对于新药发现至关重要。然而,大多数药物具有特异性问题,因为它们与Keap1的半胱氨酸残基共价结合,导致脱靶效应。因此,直接抑制Keap1-Nrf2PPIs是一个新的研究思路。通过非亲电和非共价结合,其抑制剂具有更好的特异性和激活Nrf2的能力,针对Keap1-Nrf2PPI的靶向治疗已成为慢性疾病药物开发的新方法。本文综述了Keap1相关通路的成员和下游基因及其在炎症性疾病模型中的作用。此外,本文总结了2010-2024年以Keap1为靶点的抗炎药物的研究进展,分子作用机制,以及在炎症性疾病中的治疗作用。
Inflammation is a protective mechanism against endogenous and exogenous pathogens. It is a typical feature of numerous chronic diseases and their complications.
Keap1 is an essential target in oxidative stress and inflammatory diseases. Among them, the
Keap1-Nrf2-ARE pathway (including
Keap1-Nrf2-HO-1) is the most significant pathway of
Keap1 targets, which participates in the control of inflammation in multiple organs (including renal inflammation, lung inflammation, liver inflammation, neuroinflammation, etc.). Identifying new
Keap1 inhibitors is crucial for new drug discovery. However, most drugs have specificity issues as they covalently bind to cysteine residues of Keap1, causing off-target effects. Therefore, direct inhibition of
Keap1-Nrf2 PPIs is a new research idea. Through non-electrophilic and non-covalent binding, its inhibitors have better specificity and ability to activate Nrf2, and targeting therapy against Keap1-Nrf2 PPIs has become a new method for drug development in chronic diseases. This review summarizes the members and downstream genes of the Keap1-related pathway and their roles in inflammatory disease models. In addition, we summarize all the research progress of anti-inflammatory drugs targeting Keap1 from 2010 to 2024, mainly describing their biological functions, molecular mechanisms of action, and therapeutic roles in inflammatory diseases.